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Nucleic Acids Res ; 44(1): 134-51, 2016 Jan 08.
Article in English | MEDLINE | ID: mdl-26358810

ABSTRACT

Mycobacterium tuberculosis (Mtb) Cmr (Rv1675c) is a CRP/FNR family transcription factor known to be responsive to cAMP levels and during macrophage infections. However, Cmr's DNA binding properties, cellular targets and overall role in tuberculosis (TB) complex bacteria have not been characterized. In this study, we used experimental and computational approaches to characterize Cmr's DNA binding properties and identify a putative regulon. Cmr binds a 16-bp palindromic site that includes four highly conserved nucleotides that are required for DNA binding. A total of 368 binding sites, distributed in clusters among ~200 binding regions throughout the Mycobacterium bovis BCG genome, were identified using ChIP-seq. One of the most enriched Cmr binding sites was located upstream of the cmr promoter, and we demonstrated that expression of cmr is autoregulated. cAMP affected Cmr binding at a subset of DNA loci in vivo and in vitro, including multiple sites adjacent to members of the DosR (DevR) dormancy regulon. Our findings of cooperative binding of Cmr to these DNA regions and the regulation by Cmr of the DosR-regulated virulence gene Rv2623 demonstrate the complexity of Cmr-mediated gene regulation and suggest a role for Cmr in the biology of persistent TB infection.


Subject(s)
Bacterial Proteins/metabolism , Cyclic AMP/metabolism , Mycobacterium tuberculosis/genetics , Mycobacterium tuberculosis/metabolism , Protein Kinases/metabolism , Transcription Factors/metabolism , Amino Acid Motifs , Animals , Bacterial Proteins/chemistry , Bacterial Proteins/genetics , Binding Sites , Cattle , Chromatin Immunoprecipitation , DNA/metabolism , DNA-Binding Proteins , Gene Expression Regulation, Bacterial , Gene Knockout Techniques , Humans , Mycobacterium bovis/genetics , Mycobacterium bovis/metabolism , Position-Specific Scoring Matrices , Protein Binding , Protein Interaction Domains and Motifs , Protein Multimerization , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , SELEX Aptamer Technique , Transcription Factors/chemistry , Transcription Factors/genetics
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